Segregation analysis of Alzheimer pedigrees: Rare mendelian dominant mutation(s) explain a minority of early-onset cases

Segregation analysis of Alzheimer disease (AD) in 92 families ascertained through early-onset (less than or equal to age 60 years) AD (EOAD) probands has been carried out, allowing for a mixture in AD inheritance among probands, The goal was to quantify the proportion of probands that could be explained by autosomal inheritance of a rare disease allele "a" at a Mendelian dominant gene (MDG), Our data provide strong evidence for a mixture of two distributions; AD transmission is fully explained by MDG inheritance in <20% of probands, Male and female age-of-onset distributions are significantly different for "AA" but not for "aA" subjects. For "aA" subjects the estimated penetrance value was close to 1 by age 60, For "AA" subjects, it reaches, by age 90, 10% (males) and 30% (females), We show a clear cutoff in the posterior probability of being an MDG case. (C) 1996 Wiley-Liss, Inc.